Process for carbapenem synthesis

ABSTRACT

A process for synthesizing a compound represented by formula I:  
                 
 
     or a pharmaceutically acceptable salt thereof, wherein deprotection is conducted using a prereduced metal catalyst is disclosed.

BACKGROUND OF THE INVENTION

[0001] The present invention relates to a process for synthesizingcarbapenem intermediates and compounds.

[0002] The carbapenems are among the most broadly effective antibioticsmaking them useful in the treatment of a wide range of bacterialinfections. The continuing emergence of bacteria exhibiting resistanceto existing therapeutic agents has made development of new carbapenemsan important part of our strategy in addressing this problem.

[0003] The process developed for the manufacture of the carbapenemantibiotics disclosed herein is known to make use of apalladium-catalyzed hydrogenolysis of a p-nitrobenzyl ester. Thereaction is conducted at pH 6.5 to 8.5 to minimize degradation of theproduct. Filtration in this pH range to remove the solid catalystfollowing the reaction results in a solution containing unacceptablyhigh levels of palladium. This problem has been solved in the past byadjusting the pH to below 6 prior to filtration. This pH adjustment,however, results in degradation of the product and introduces salts,which must be removed prior to isolation of the product.

[0004] This invention relates to a process that utilizes prereducedcatalysts to achieve a significantly lower level of solubilized metalderived from the catalyst following the reaction.

SUMMARY OF THE INVENTION

[0005] A process for synthesizing a compound represented by formula I:

[0006] or a pharmaceutically acceptable salt thereof, is disclosed,wherein R¹ and R² independently are H, C₁₋₁₀ alkyl, aryl or heteroaryl,substituted or unsubstituted, comprising deprotecting a compound offormula II:

[0007] by hydrogenolysis in the presence of a prereduced metal catalyst,purifying and isolating the compound of formula I, wherein P is acarboxyl protecting group, P* is H, H₂ ⁺, or a protecting group whichcan be removed by hydrogenolysis such as carbobenzyloxy (CBZ), orp-nitrobenzyl carbamoyl (PNZ), and R¹ and R² are as described above.

[0008] These and other aspects of the invention can be realized uponcomplete review of the application.

DETAILED DESCRIPTION OF THE INVENTION

[0009] The invention is described herein in detail using the termsdefined below unless otherwise specified.

[0010] The term “alkyl” refers to a monovalent alkane (hydrocarbon)derived radical containing from 1 to 15 carbon atoms unless otherwisedefined. It may be straight or branched, and when of sufficient size,e.g., C₃₋₁₅ may be cyclic. Preferred straight or branched alkyl groupsinclude methyl, ethyl, propyl, isopropyl, butyl and t-butyl. Preferredcycloalkyl groups include cyclopropyl, cyclopentyl and cyclohexyl.

[0011] Alkyl also includes an alkyl group substituted with a cycloalkylgroup such as cyclopropylmethyl.

[0012] Alkyl also includes a straight or branched alkyl group whichcontains or is interrupted by a cycloalkylene portion. Examples includethe following:

[0013] wherein: x′ and y′=from 0-10; and w and z=from 0-9.

[0014] When substituted alkyl is present, this refers to a straight,branched or cyclic alkyl group as defined above, substituted with 1-3groups as defined with respect to each variable.

[0015] Aryl refers to aromatic rings e.g., phenyl, substituted phenyland like groups as well as rings which are fused, e.g., naphthyl and thelike. Aryl thus contains at least one ring having at least 6 atoms, withup to two such rings being present, containing up to 10 atoms therein,with alternating (resonating) double bonds between adjacent carbonatoms. The preferred aryl groups are phenyl and naphthyl. Aryl groupsmay likewise be substituted as defined below. Preferred substitutedaryls include phenyl and naphthyl substituted with one to three groups.

[0016] The term “heteroaryl” refers to a monocyclic aromatic hydrocarbongroup having 5 to 6 ring atoms, or a bicyclic aromatic group having 8 to10 atoms, containing at least one heteroatom, O, S or N, in which acarbon or nitrogen atom is the point of attachment, and in which oneadditional carbon atom is optionally replaced by a heteroatom selectedfrom O or S, and in which from 1 to 3 additional carbon atoms areoptionally replaced by nitrogen heteroatoms. The heteroaryl group isoptionally substituted with up to three groups.

[0017] Heteroaryl includes aromatic and partially aromatic groups whichcontain one or more heteroatoms. Examples of this type are thiophene,purine, imidazopyridine, pyridine, oxazole, thiazole, oxazine, pyrazole,tetrazole, imidazole, pyridine, pyrimidine, pyrazine and triazine.Examples of partially aromatic groups aretetrahydroimidazo[4,5-c]pyridine, phthalidyl and saccharinyl, as definedbelow.

[0018] Substituted alkyl, aryl and heteroaryl, and the substitutedportions of aralkyl, aralkoxy, heteroaralkyl, heteroaralkoxy and likegroups are substituted with from 1-3 groups selected from the groupconsisting of: halo, hydroxy, cyano, acyl, acylamino, aralkoxy,alkylsulfonyl, arylsulfonyl, alkylsulfonylamino, arylsulfonylamino,alkylaminocarbonyl, alkyl, alkoxy, aryl, aryloxy, aralkoxy, amino,alkylamino, dialkylamino, carboxy, trifluoromethyl and sulfonylamino.

[0019] Halo means Cl, F, Br and I selected on an independent basis.

[0020] A preferred process for synthesizing a compound represented byformula Ia:

[0021] or a pharmaceutically acceptable salt thereof, is disclosed,comprising deprotecting a compound of formula IIa:

[0022] by hydrogenolysis in the presence of a prereduced metal catalyst,purifying and isolating the compound of formula Ia, wherein P is acarboxyl protecting group, P* is H, H₂ ⁺, or a protecting group whichcan be removed by hydrogenolysis such as carbobenzyloxy (CBZ), orp-nitrobenzyl carbamoyl (PNZ), and X⁺ is a charge-balancing group. Byusing a prereduced catalyst, the levels of solubilized metal derivedfrom the catalyst are significantly lower compared with the use of anunreduced catalyst. The level of solubilized metal is negligible in thesense that it is possible to isolate the compound of formula Icontaining pharmaceutically acceptable levels of the metal derived fromthe catalyst, said levels would expose a patient to no more than about50 micrograms per day of the metal, preferably no more than 25micrograms per day. Examples of the metal catalysts are those describedherein.

[0023] In another aspect of the invention a process for synthesizing acompound represented by formula I:

[0024] or a pharmaceutically acceptable salt thereof, containingpharmaceutically acceptable levels of a metal derived from a metalcatalyst is disclosed, wherein R¹ and R² independently are H, C₁₋₁₀alkyl, aryl or heteroaryl, said alkyl, aryl or heteroaryl beingsubstituted or unsubstituted, comprising deprotecting a compound offormula II:

[0025] by hydrogenolysis in the presence of a prereduced metal catalyst,purifying and isolating the compound of formula I, wherein P is acarboxyl protecting group, P* is H, H₂ ⁺, or a protecting group whichcan be removed by hydrogenolysis, and R¹ and R² are as described above.A preferred aspect of this process is realized when it is conducted witha compound of formula IIa to produce a compound of formula Ia.

[0026] The compounds of formula I and Ia′ can be obtained as shown belowin Flow Sheets A-1 and A-2, respectively.

[0027] Flow sheet A-2 below provides a preferred process as it relatesto 1β-methylcarbapenems.

[0028] Compounds 1, 1a, 2 and 2a can be obtained in accordance withtechniques such as those disclosed in U.S. Pat. Nos. 5,034,384, grantedon Jul. 23, 1991; 5,952,323, granted on Sep. 14, 1999; 4,994,568 grantedon Feb. 19, 1991; 4,269,772 granted on May 26, 1981; 4,350,631 grantedon Sep. 21, 1982; 4,383,946 granted on May 17, 1983; 4,414,155 grantedon Nov. 8, 1983; 6,063,931, granted May 16, 2000; EP-A-562855;Tetrahedron Lett. 21, 2783 (1980); J. Am. Chem. Soc. 102, 6161 (1980);J. Am. Chem. Soc. 108, 4675 (1986) and U.S. Pat. No. 5,478,820 grantedon Dec. 26, 1995. The teachings of these references are incorporatedherein by reference. Compounds of formula I and Ia and derivativesthereof and processes thereof are disclosed in U.S. Pat. Nos. 5,872,250,granted Feb. 16, 1999 and 6,180,783, granted Jan. 30, 2001, bothincorporated herein by reference.

[0029] The compounds of formula II or IIa′ or salts thereof are producedby reacting the enol phosphate 1 or 1a and thiol 2 or 2a in the presenceof a base. This reaction is typically conducted at reduced temperature,e.g., about −30° C. to about −70° C., preferably about −40° C. to about−60° C. Bases which are suitable for the above reaction include organicas well as inorganic bases. Preferred bases for use herein are secondaryand tertiary amines such as diisopropylamine (DIPA), dicyclohexylamine(DCHA), 2,2,6,6-tetramethylpiperidine (TMP), guanidines such as1,1,3,3-tetramethylguanidine (TMG),N,N,N′,N′N″-tetraethylcyclohexylguanidine (TECHG),N,N′,N″,N″-dicyclohexyldiethylguanidine (DCDEG) and amidines such as1,8-diazabicyclo[4.3.0]undec-7-ene (DB) and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN). Most preferable bases are the guanidine basesand even more preferred is TMG.

[0030] An antioxidant is optionally added. Preferred antioxidants arePR₃, wherein R₃ belongs to the group consisting of C₁₋₈ alkyl, aryl orheteroaryl, or aromatic phenols such as BHT (butylated hydroxy toluene)and BHA (butylated hydroxy anisole). Most preferred antioxidant is PBu₃.

[0031] The reaction can be conducted in a polar organic solvent, e.g.,N-ethylpyrrolidinone NEP), N-methylpyrrolidinone, N,N-dimethylformamide(DMF), N,N-dimethylacetamide (DMA), acetonitrile, propionitrile, or amixture thereof and the like. The preferred solvent isN-ethylpyrrolidinone (NEP).

[0032] After coupling, the carbapenem can be stabilized by combining thecarbapenem with a carbon dioxide source. Stabilization can be conductedaccording to the teachings in U.S. Pat. No. 6,180,783, granted Jan. 30,2001 and incorporated by reference herein.

[0033] The carbapenem is subjected to deprotection, thus removing the3-carboxyl protecting group yielding I or Ia′.

[0034] In the claimed invention, hydrogenolysis is conducted in thepresence of a prereduced metal catalyst. The preferred reaction involvesH₂ gas with a prereduced palladium (Pd on carbon) catalyst. The reactioncan be conducted under hydrogen over a broad pressure range, preferablyabove 40 psi. A base such as sodium hydroxide or sodium bicarbonate canbe added during the reaction to control pH. Sufficient sodiumbicarbonate can be present at the start of the reaction to control thepH. Preferably, the reaction is conducted in the presence of a source ofcarbon dioxide such as sodium bicarbonate to give the stabilized form 3or 3a where X⁺ is a charge-balancing group.

[0035] Suitable catalysts are those which contain a metal known to beuseful for catalytic hydrogenation such as palladium (Pd), platinum(Pt), and rhodium (Rh), preferably Pd. The metal catalyst can be a saltor metal powder or supported on a wide range of solid supports known tobe useful in catalytic hydrogenation reactions including alumina,silica, calcium carbonate, barium carbonate, barium sulfate, strontiumcarbonate, polymers, or carbon, preferably activated carbon. Thecatalyst is used in an amount that is at least 5 mol % relative to thecarbapenem substrate. A pre-reduced catalyst is formed by chemicaltreatment with a reducing agent prior to addition of the substrate.Suitable reducing agents include those known to be useful for thereduction of metal catalysts such as formate, borohydride, and hydrogen,preferably hydrogen. The reduction can be performed in manufacture ofthe catalyst or just prior to use. The pH can be controlled duringreduction by addition of a base. Preferred bases are sodium hydroxide orsodium bicarbonate.

[0036] Carbon dioxide sources, as used herein, refer to carbon dioxidegas as well as compounds which can produce carbon dioxide in solution.Representative examples include carbonates and bicarbonates, such assodium carbonate, sodium bicarbonate, potassium carbonate and potassiumbicarbonate. Preferably, the carbon dioxide source is sodiumbicarbonate. The sodium bicarbonate can be purchased or obtained bymixing sodium hydroxide and carbon dioxide at a pH above about 6.5. Thecarbon dioxide source can alternatively be included in the reactionmedium prior to or added during the deprotection reaction.

[0037] Examples of suitable 3-carboxyl protecting groups are those whichcan be removed by hydrogenolysis. Examples of such protecting groupsare: benzhydryl, o-nitrobenzyl, p-nitrobenzyl, 2-naphthylmethyl, andbenzyl. A preferred carboxyl protecting group is p-nitrobenzyl (PNB).Many other suitable protecting groups are known in the art. See, e.g.,T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons,Inc., 1981 (Chapters 2 and 5).

[0038] Numerous salt-forming ions are recited in Berge, S. M., et al. J.Pharm. Sci. 66(1): 1-16 (1977), the teachings of which are incorporatedherein by reference. The charge balancing group X⁺ maintains overallcharge neutrality. Preferably X⁺ represents a pharmaceuticallyacceptable salt-forming cation. Preferred salt-forming cations areselected from the group consisting of: sodium, potassium, calcium andmagnesium. More preferably the salt-forming cation is a member selectedfrom the group consisting of: Na⁺, Ca⁺² and K⁺.

[0039] The salt-forming cations mentioned above provide electronicbalance and overall charge neutrality. From zero to three positivelycharged counterions may be present depending upon the number of chargedmoieties on the carbapenem. The number of negatively charge groups islargely a function of pH, since these groups become protonated as the pHis lowered. For every positively charged functional group on themolecule, a negatively charged counterion is present to provide overallcharge neutrality. Different counterions may also be included in theoverall reaction composition. Hence, for example, calcium and sodiumcould be included together in the reaction to provide overall chargeneutrality. The counterions can thus be varied within wide limits.Generally, the counterion or counterions are pharmaceutically acceptablecationic species.

[0040] The compounds formed in the present invention have asymmetriccenters and occur as racemates, racemic mixtures, and as individualdiastereomers. The processes of synthesizing all such isomers, includingoptical isomers, are included in the present invention.

[0041] Purification and isolation of compounds of formula I and Ia canbe achieved via a combination of several operations: extractions usingsolvents such as dichloromethane to remove residual organic solvents,chromatography using hydrophobic resin chromatography (eluting with 0.05M sodium bicarbonate at about 5° C.), nanofiltration for concentrationof the process stream followed by crystallization of the pure drug (SeeU.S. Ser. No. 09/093813, filed Jun. 9, 1998, incorporated herein byreference).

[0042] Alternatively, the column chromatography and nanofiltrationoperations can be eliminated when the extraction is carried out with anappropriate alcohol. A preferred extraction is carried out with theappropriate alcohol in the presence of an ion-pairing reagent. Theprocess described below allows a direct crystallization of carbapenemcompounds after this type of extraction.

[0043] The extractions can be conducted by methods generally known inthe art. A preferred extraction process is discussed in U.S. Ser. No.09/487,044 filed Jan. 19, 2000, which is incorporated herein byreference. An example of the extraction involves extracting a solutioncontaining a compound of formula I, Ia, 3, or 3a, or a pharmaceuticallyacceptable salt thereof, wherein each X⁺ is a charge-balancing group andis present or absent as necessary to provide overall charge neutrality,with an alcohol, crystallizing and collecting a compound of formula I orIa′from the resultant aqueous phase. It is preferable that theextraction is conducted in the presence of an ion-pairing reagent andthat pH of the aqueous phase is maintained between neutral and mildlybasic pH (pH 7 to 9) according to the teachings of WO 9745430. It isalso preferable that the extraction is performed while I or Ia isstabilized in the form, 3 or 3a. After extraction, the stabilized form 3or 3a is readily converted to a salt form of I or Ia under neutral tomildly acidic conditions (pH 7 to 5). The pH is adjusted to produce theappropriate salt form of I or Ia for isolation by crystallization.Alternatively, there can be multiple extractions with, for example theexample solvents being isoamyl alcohol (IAA)/DPP solution in the firstextraction, and IAA in a second extraction.

[0044] It is preferable to use equipment that is capable of multi-stageextraction such as mixer-settler cascade, spray tower, baffle tower,packed tower, perforated plate tower, mechanically agitated extractor,pulsed extractor, reciprocating plate extractor, or centrifugalextractor for optimal performance. Most preferable is the use of amulti-stage centrifugal extractor. The preferred equipment is dependenton scale; CINC (Costner Industries Nevada Corporation) liquid-liquidcentrifugal separators are preferred for laboratory scale operation;whereas, a Podbielniak® centrifugal extractor is preferred for largescale operation.

[0045] Use of these multi-stage centrifugal extractor providesunexpected benefits. For example, the ion pairing reaction of TMG withdiphenyl phosphate (DPP) is used to reduce the TMG level in the processstream prior to the isolation of the compound of formula I, Ia, 3 or 3a.In addition to this purification, the residual reaction solvent, N-ethylpyrrolidinone (NEP) must be removed from the process stream, and theprocess stream must be concentrated four fold to allow successfulcrystallization of the compound of formula I, Ia, 3 or 3a. All three ofthese processing requirements are accomplished simultaneously via arapid, multi-stage, counter-current centrifugal extraction, whichminimizes the soluble product degradation during processing.

[0046] The alcohol useful for the present invention includes but is notlimited to iso-amyl alcohol, tert-amyl alcohol, 1-butanol, 2-butanol,1-octanol, 1-hexanol, 1-heptanol, cyclohexanol, 1-pentanol,cyclopentanol, 2-pentanol, 2-methyl-1-pentanol, 2-ethyl-1-butanol,4-methyl-2-pentanol, 2,6-dimethyl-4-heptanol, 2-methylcyclohexanol,preferably 1-butanol or iso-amyl alcohol.

[0047] Preferred ion-pairing reagents for use in the present inventionare C₆₋₂₄ carboxylic acids, phosphoric acids, phosphinic acids, sulfonicacids and the like and their salts. Most preferred ion-pairing reagentsare the sodium salts of diphenylphosphoric acid, stearic acid ordodecylbenzenesulfonic acid.

EXAMPLE

[0048]

[0049] A hydrogenator is charged with 63 g of 10% Pd on carbon catalyst(dry weight) in 1.8 L of water. The vessel is placed under hydrogen thenvented and placed under nitrogen. Sodium hydroxide (68 g, 50%) ischarged adjusting the pH to about 7.5 with carbon dioxide.

[0050] The enol phosphate (170 g) and the thiol (86 g) are dissolved in1.3 L of N-ethylpyrrolidinone (NEP). The mixture is cooled to below −40°C. and 1,1,3,3-tetramethylguanidine (109 g) is added. After 3 hours, thereaction mixture is quenched into the hydrogenator at below 15° C.adjusting the pH to about 8 with carbon dioxide. The vessel is placedunder hydrogen. When the reaction is complete, the hydrogen is ventedand the reaction mixture is treated with activated carbon and filtered.The filtrate is extracted with iso-amyl alcohol containingdiphenylphosphoric acid (240 g) and 50% NaOH (44 g). The resultingaqueous solution is further extracted with iso-amyl alcohol to give anaqueous solution containing at least 90 mg/mL of the product. Bothextractions are performed using two CINC centrifugal separators set inseries for countercurrent extraction. The pH is adjusted to 5.5 withacetic acid. The product is crystallized by adding equal volumes ofmethanol and 1-propanol at below −5° C. and isolated by filtration. Thesolid is washed with a mixture of 2-propanol and water (85:15 v/v) thendried to yield a compound of formula Ia′.

[0051] While certain preferred embodiments of the invention have beendescribed herein in detail, numerous alternative embodiments arecontemplated as falling within the scope of the appended claims.Consequently the invention is not to be limited thereby.

What is claimed is:
 1. A process for synthesizing a compound representedby formula I:

or a pharmaceutically acceptable salt thereof, wherein R¹ and R²independently are H, C₁₋₁₀ alkyl, aryl or heteroaryl, said alkyl, arylor heteroaryl being substituted or unsubstituted, comprisingdeprotecting a compound of formula II:

by hydrogenolysis in the presence of a prereduced metal catalyst andbase to give the compound of formula I, followed by purifying andisolating the compound of formula I, wherein P is a carboxyl protectinggroup, P* is H, H₂ ⁺, or a protecting group which can be removed byhydrogenolysis, and R¹ and R² are as described above.
 2. A processaccording to claim 1 wherein the protecting group is carbobenzyloxy orp-nitrobenzyl carbamoyl (PNZ).
 3. A process according to claim 1 whereinone of R¹ or R² is hydrogen and the other is an aryl substituted withCO₂H.
 4. A process according to claim 1 wherein the prereduced metalcatalyst is a palladium, platinum or rhodium catalyst.
 5. A processaccording to claim 4 wherein the metal catalyst is a salt or metalpowder or supported on solid supports selected from the group consistingof alumina, silica, calcium carbonate, barium carbonate, barium sulfate,strontium carbonate, polymers, or carbon.
 6. A process according toclaim 5 wherein the metal catalyst is prereduced palladium on carbon. 7.A process according to claim 1 wherein the base is bicarbonate orhydroxide and carbon dioxide mixed to make bicarbonate.
 8. A processaccording to claim 6 further comprising purifying the compound usinghydrophobic resin chromatography.
 9. A process according to claim 8further comprising concentrating the compound in solution using ananofiltration membrane.
 10. A process according to claim 9 furthercomprising crystallizing the compound.
 11. A process according to claim1 wherein the purification step consists of treatment with activatedcarbon.
 12. A process according to claim 6 further comprising extractinga solution containing a compound of formula I or 3:

or a pharmaceutically acceptable salt thereof, wherein each X⁺ is acharge-balancing group, and R¹ and R² are as described above with aC₄₋₁₀ alcohol, purifying and isolating the compound of formula I fromthe resulting aqueous phase.
 13. A process according to claim 12 whereinthe extraction is conducted with an alcohol in the presence of anion-pairing reagent, while maintaining a pH of the aqueous phase betweenneutral and mildly basic.
 14. A process according to claim 13 whereinthe extraction is conducted using a multi-stage extractor.
 15. A processaccording to claim 14 wherein the extraction is conducted using amulti-stage countercurrent centrifugal extractor.
 16. A process inaccordance with claim 13 wherein the alcohol is iso-amyl alcohol,tert-amyl alcohol, 1-butanol, 2-butanol, 1-octanol, 1-hexanol,1-heptanol, cyclohexanol, 1-pentanol, cyclopentanol, 2-pentanol,2-methyl-1-pentanol, 2-ethyl-1-butanol, 4-methyl-2-pentanol,2,6-dimethyl-4-heptanol, or 2-methylcyclohexanol.
 17. A process inaccordance with claim 16 wherein the alcohol is iso-amyl alcohol or1-butanol.
 18. A process in accordance with claim 13 wherein theion-pairing reagent comprises C₆₋₂₄ carboxylic acids, phosphoric acids,phosphinic acids, sulfonic acids or their salts.
 19. A process inaccordance with claim 17 wherein ion-pairing reagent is a sodium salt ofdiphenylphosphoric acid, stearic acid or dodecylbenzenesulfonic acid.20. A process according to claim 12 wherein the extracted solutioncontains a compound of formula I.
 21. A process according to claim 12wherein the extracted solution contains a compound of formula
 3. 22. Aprocess for synthesizing a compound represented by formula Ia:

or a pharmaceutically acceptable salt thereof, is disclosed comprisingdeprotecting a compound of formula IIa:

by hydrogenolysis in the presence of a prereduced metal catalyst andbase to give a compound of formula Ia, followed by purifying andisolating the compound of formula Ia, wherein P is a carboxyl protectinggroup, P* is H, H₂ ⁺, or a protecting group which can be removed byhydrogenolysis, and X⁺ is a charge-balancing group.
 23. A process inaccordance with claim 22 wherein the P* protecting group, iscarbobenzyloxy or p-nitrobenzyl carbamoyl (PNZ).
 24. A process accordingto claim 22 wherein the prereduced metal catalyst is a palladium,platinum or rhodium catalyst.
 25. A process according to claim 24wherein the metal catalyst is a salt or metal powder or supported onsolid supports selected from the group consisting of alumina, silica,calcium carbonate, barium carbonate, barium sulfate, strontiumcarbonate, polymers, or carbon.
 26. A process according to claim 25wherein the metal catalyst is prereduced palladium on carbon.
 27. Aprocess according to claim 22 wherein the base is bicarbonate orhydroxide and carbon dioxide mixed to make bicarbonate.
 28. A processaccording to claim 22 wherein the purification step consists oftreatment with activated carbon.
 29. A process according to claim 25further comprising purifying the compound using hydrophobic resinchromatography.
 30. A process according to claim 28 further comprisingconcentrating a solution of the compound using a nanofiltrationmembrane.
 31. A process according to claim 29 further comprisingcrystallizing the compound.
 32. A process according to claim 26 furthercomprising purifying the compound by extracting a solution containing acompound of formula Ia or 3a:

or a pharmaceutically acceptable salt thereof, wherein each X⁺ is acharge-balancing group, with a C₄₋₁₀ alcohol, crystallizing andcollecting a compound of formula Ia′ from the resulting aqueous phase.33. A process according to claim 32 wherein the extraction is conductedwith an alcohol in the presence of an ion-pairing reagent whilemaintaining a pH of the aqueous phase between neutral and mildly basic.34. A process according to claim 33 wherein the extraction is conductedusing a multi-stage extractor.
 35. A process according to claim 34wherein the extraction is conducted using a multi-stage countercurrentcentrifugal extractor.
 36. A process in accordance with claim 33 whereinthe alcohol is iso-amyl alcohol, tert-amyl alcohol, 1-butanol,2-butanol, 1-octanol, 1-hexanol, 1-heptanol, cyclohexanol, 1-pentanol,cyclopentanol, 2-pentanol, 2-methyl-1-pentanol, 2-ethyl-1-butanol,4-methyl-2-pentanol, 2,6-dimethyl-4-heptanol, or 2-methylcyclohexanol.37. A process in accordance with claim 36 wherein the alcohol isiso-amyl alcohol or 1-butanol.
 38. A process in accordance with claim 33wherein the ion-pairing reagent comprises C₆₋₂₄ carboxylic acids,phosphoric acids, phosphinic acids, sulfonic acids or their salts.
 39. Aprocess in accordance with claim 38 wherein the ion-pairing reagent is asodium salt of diphenylphosphoric acid, stearic acid ordodecylbenzenesulfonic acid.
 40. A process according to claim 32 whereinthe extracted solution contains a compound of formula 3a:


41. A process according to claim 32 wherein the extracted solutioncontains a compound of formula Ia:


42. A process for synthesizing a compound represented by formula I:

or a pharmaceutically acceptable salt thereof, containingpharmaceutically acceptable levels of a metal derived from a metalcatalyst, wherein R¹ and R² independently are H, C₁₋₁₀ alkyl, aryl orheteroaryl, said alkyl, aryl or heteroaryl being substituted orunsubstituted, comprising deprotecting a compound of formula II:

by hydrogenolysis in the presence of a prereduced metal catalyst andbase to give a compound of formula I, followed by purifying andisolating the compound of formula I, wherein P is a carboxyl protectinggroup, P* is H, H₂ ⁺, or a protecting group which can be removed byhydrogenolysis, and R¹ and R² are as described above.
 43. A processaccording to claim 42 for synthesizing a compound represented by formulaIa:

or a pharmaceutically acceptable salt thereof, containingpharmaceutically acceptable levels of a metal derived from a metalcatalyst, comprising deprotecting a compound of formula IIa:

by hydrogenolysis in the presence of a prereduced metal catalyst andbase to give a compound of formula Ia, followed by purifying andisolating the compound of formula Ia, wherein P is a carboxyl protectinggroup, P* is H, H₂ ⁺, or a protecting group which can be removed byhydrogenolysis.